Method of drying a lactulose solution

ABSTRACT

A method of drying a lactulose solution comprises introducing the solution into a vacuum chamber at elevated temperature and at reduced pressure so that the solution forms a foam, drying the foam under reduced pressure, and milling or grinding or breaking the dried foam into powder.

The present invention relates to a method of drying a solution, inparticular to a method of drying a lactulose solution so as to obtain apowder which can be reconstituted with water to form a lactulosesolution.

Lactulose is a synthetic disaccharide that consists of fructose andgalactose. As there is no corresponding disaccharidase in the humanintestinal mucosal cells, lactulose is not split in the small intestineand therefore is not absorbed. In the colon, it is metabolised toorganic acids in short chains (acetic and lactic acids) by the gutflora. This fermentation acidifies the content of the intestine and hasan osmotic effect; the higher the dose, the stronger the osmotic effect.Hence, lactulose solutions are used as laxatives. Lactulose preparationsthat are commercially available also include quantities of galactose,lactose, and other sugars.

A problem with lactulose solutions is that they are awkward totransport—typical lactulose solutions contain about 30 percent by waterand hence a large amount of weight that is transported is made up ofthis water. It would be preferable for a powdered or other dryformulation of lactulose to be transported, and hence a number ofproposals have been made to dry lactulose solutions. All of theseproposals have specific disadvantages.

U.S. Pat. No. 3,716,408 describes a lactulose powder containing 55percent or above lactulose obtained by spray drying. It is necessary toincorporate an amount of an agent to promote drying of the lactulose,specifically konnyaku powder, into the solution in order for drying tobe successful. However, it is highly undesirable for pharmaceuticalpreparations to include any such additional agents.

U.S. Pat. No. 5,326,405 describes a method for preparation ofcrystal-water-free lactulose by simultaneous stirring and heating of alactulose solution to reduce its water content and introduction of seedcrystals until a free-flowing powder is obtained. A disadvantage of thismethod is that it needs to be carried out in batches and is not suitablefor commercial scale production. Additionally, there is the need tointroduce seed crystals and these crystals may contaminate or bedifferent form the content of the lactulose solution, as well asintroducing a further step into the process.

U.S. Pat. No. 5,415,695 describes a further method of preparing solidforms of lactulose by evaporating lactulose syrup to reduce its watercontent and then cooling the evaporated syrup until it solidifies. Thesolidified product can then be milled into powder. The method ispreferably carried out with very rapid cooling of the lactulosesolution. This often results in a product that needs extensive millingor other processing to obtain a uniform powder. Further, it is notpossible to carry out this process in a continuous fashion.

A still further process for manufacturing solid lactulose preparationsis described in WO 98/19684. An aqueous lactulose solution isspray-dried in a countercurrent of air into a fluidised bed container.However, to obtain reliable output of dried lactulose it is generallynecessary for a swelling or gelling agent to be included to absorb waterfrom the lactulose solution. As previously mentioned, the presence ofany such agent is highly undesirable in pharmaceutical preparationscontaining lactulose.

JP49-54556 describes a method for drying lactulose syrup in a shelf-typefreeze dryer at temperatures of >−45° C. under reduced pressure. In thisprocess, a batch of lactulose is spread onto a tray, freeze-dried to80-85% solids, and then warmed gradually to form a foam, which is driedunder reduced pressure at a temperature of 80° C. for 4 hours, followedby a temperature of 35° C. for 18 hours. This process requires longdrying times and is only suitable as a batch operation.

It is an object of the present invention to provide an alternativemethod for drying of lactulose solutions so as to obtain a powdered formof lactulose.

It is a further object of the present invention to provide a method ofdrying lactulose which does not require the presence of agents such asswelling or drying agents or seed crystals.

Accordingly, a first aspect of the present invention provides a methodof drying a lactulose solution comprising introducing the solution intoa vacuum chamber at elevated temperature and at reduced pressure so thatthe solution forms a foam, and drying the foam to obtain a driedlactulose-containing composition.

It has advantageously been found that the foam obtained can be dried,typically under reduced pressure, to obtain a powdered form of lactulosewithout the need for swelling or drying agents and without the need forseed crystals. Thus, the lactulose powder obtained by the method of theinvention is eminently suitable for pharmaceutical compositions, and issuitable for reconstitution with water to provide a lactulose solution.

The dried product obtained using the invention has a number ofadvantages. It is lighter than the currently available syrup and easierto measure in accurate doses. Bottles of syrup are liable to break,whereas packets of powder avoid this problem. The powder can bereconstituted with tap water to provide a dosage solution—10 to 15 g ina cap of water, about 200 ml, is typical.

In an example of use of the invention, a lactulose solution having atleast 80 percent solids by weight is introduced into a vacuum chamber atelevated temperature and at reduced pressure so that the solution formsa foam. This foam is dried under reduced pressure and a powder thenobtained by milling or grinding or breaking the dried foam. Theresultant powder typically has a moisture content of less than 10% andpreferably less than 8%, most preferably less than 6%, and is in theform of a white, granular powder that is free flowing and can bepackaged directly without further treatment. Upon reconstitution withwater the powder forms a lactulose solution.

Prior to drying, the lactulose solution is suitably maintained outsidethe vacuum chamber at about atmospheric pressure and ambienttemperature. Solution is then fed into the vacuum chamber and uponencountering conditions of elevated temperature and reduced pressurewithin the chamber expands into a foam. In this foam the profusion ofbubbles that are created means that compared to the solution a verylarge surface area is presented to the environment inside the vacuumchamber and the lactulose solution has been spread out into a largenumber of thin films that make up the bubbles and other parts of thefoam; the solution has thus been converted into a form suitable fordrying.

In the method of the invention, the highest temperature is generally atthe point of entry into the chamber and the method comprises extrudingthe solution through a nozzle so that the solution foams as it exits thenozzle and enters the environment of the chamber. The invention issuited to be carried out continuously and in an embodiment of theinvention the drying is carried out using a moving belt onto which isdeposited the lactulose foam exiting from the nozzle. The belt movesforwards, away from the nozzle, so creating space for further foam thatcontinues to exit from the nozzle. In a specific embodiment of theinvention, as the belt moves forwards so the nozzle moves back and forthacross the belt covering a portion of or the whole of the width of thebelt with foam. By the time the nozzle has travelled from one side tothe other and returned the belt has advanced sufficiently to providespace for a further line of foam to be deposited. Thus, most preferably,the method is carried out in a vacuum belt dryer and comprises evenlydistributing the solution over the belt of the dryer as the belt ismoved. A non-stick coating on the belt, such as a Teflon coating ispreferred, for ease of removing dried foam further along the belt.

Drying can be carried out at varying or fixed temperatures. The dryingtemperature may rise from one section of the chamber to the next andthen fall. The temperature may be chosen so that the solution does notinitially foam an entry into the chamber but does so when advanced to ahigher temperature zone. Preferably the highest temperature is at orabout the point of entry of solution into the chamber. It is furtherpreferred that the foam is dried at a temperature which is reduced covertime. Initially, when the foam is first formed at high temperature, ifthe temperature were to be reduced too quickly the foam might collapse.The temperature is thus kept fairly high for at least the first sectionof the drying stage to maintain the foam. As the water content isreduced so the foam solidifies and the temperature can be reduced inlatter stages of drying. This staged temperature drop has the advantagethat the risk of damage to the lactulose caused by excessive heating issubstantially avoided. A further advantage is that the final stage canbe chosen to be at a temperature that is at or close to ambient, wherebydried lactulose exiting the dryer can immediately be packaged andsealed, for example in plastic bags that might not be suitable toreceive hot lactulose.

The method of the invention preferably comprises passing the foamthrough a plurality of drying zones, each zone being at a differenttemperature, the temperature of the zones reducing from one zone to thenext. Foaming of the solution occurs when the combination of temperatureand pressure is such that bubbles of steam form from the water contentof the solution.

The method can advantageously comprise passing the foam through a firstzone at a temperature of at least 100° C. and passing the foam through afinal zone at a temperature of 50° C. or less. The foam may suitablyreside in each zone for at least 3 minutes. More specifically, themethod may comprise passing the foam through a first zone at atemperature of about 110-130° C. for a period of about 3-12 minutes,passing the foam through a second zone at a temperature of about 70-90°C. for a period of about 3-12 minutes and passing the foam through athird zone at a temperature of about 20-40° C. for about 3-12 minutes.The time in each zone is more preferably 4-6 minutes.

Whilst the temperature can readily be changed from one zone to the nextin a vacuum chamber, it is usually technically more difficult to providezones of differing pressure. In the method of the invention, thepressure in the vacuum chamber is usually maintained below 50 mbar, andpreferably below 40 mbar and above 5 mbar. To provide the conditionssuitable for foaming of the solution a combination of temperature andpressure is needed, and at below 50 mbar a temperature of at least 100°C. has been found to produce a good foam with at least 110° C. generallybeing used. A lower temperature may also be effective, dependent uponthe chamber pressure. Higher temperatures may also be used providedthese are not so high as to risk caramelization or other detriment tothe lactulose. Generally, with chamber pressures in the range 5-50 mbartemperature of 100-150° C. are suitable to produce the foaming of thesolution needed for satisfactory drying, though it is the combination oftemperature and pressure that is used rather than any particular valueof either. Reduced pressure can be any pressure below atmospheric.

The invention further provides a method of drying a lactulose solutioncomprising subjecting the solution to conditions of raised temperatureand reduced pressure so that the solution expands into a foam, anddrying the foam thereby produced.

In a second aspect of the present invention there is provided a methodof drying a lactulose solution by spreading out the solution into a thinfilm, and drying the film under reduced pressure. The film shouldpreferably have a thickness of no more than 2 mm. Thus, the methodcomprises forming substantially continuous thin sheets 2 mm or lessthick of the lactulose solution. These can be dried at reduced pressurewithout needing seed crystals or agents to help absorb water from thelactulose solution.

The methods of the invention are suitable for drying oflactulose-containing solutions having varying lactulose compositions.Generally, lactulose-containing solutions contain at least about 40%lactulose by weight, typically around 50 percent or more. High watercontent solutions can be dried, though when the water content of thesolution is high this means the height of foam produced in the method isincreased and this can produce impractical levels of foam in somedryers, for example if there is limited headspace above the belt.Solutions with 60 or more percent solids by weight can be dried by thepresent method. Good results have been obtained using the method of theinvention to dry a lactulose solution having 80 percent by weight solidsor more preferably at least 82 percent, made up of a combination oflactulose and optionally other sugars such as galactose, lactose,tagatose, fructose and epilactose of which the major component islactulose. In a specific embodiment of the invention, a lactulosesolution comprises 69 percent solids by weight, made up of 50 percentlactulose, 4 percent galactose, 4 percent lactose, 2 percent tagatose, 1percent fructose, 3 percent epilactose and 5 percent other sugars. Thesolids content of this solution is then reduced, such as by evaporationof water at elevated temperature, to obtain a solution having at least80 percent solids by weight, and this solution has produced good resultsin specific embodiments of the invention, leading to a dried productthat is white and free-flowing and is readily reconstituted with waterto form a lactulose solution.

The invention yet further provides, in an additional aspect, a method ofdrying a sugar-containing solution, comprising introducing the solutioninto a vacuum chamber at elevated temperature and at reduced pressure sothat the sugar-containing solution forms a foam, and drying the foamunder reduced pressure. Optionally, the dried foam can be milled orground or broken into powder. Other referred features and embodiments ofthe this further aspect of the invention correspond to the preferredfeatures and embodiments of the first aspect of the invention.

There now follows a description of specific embodiment of the invention,illustrated by the accompanying drawings in which:

FIG. 1 shows a schematic side view of apparatus for carrying out thepresent invention;

FIG. 2 shows an enlarged view of a dispenser head; and

FIG. 3 shows a view from above the dispenser head of FIG. 2.

Referring to FIGS. 1, 2 and 3 apparatus 10 comprises a movingTeflon-coated belt 11 mounted on rollers 12 for movement in thedirection shown by the arrow A. First, second and third heaters 13, 14and 15 are located immediately underneath the belt 11 and linked tocontrol apparatus (not shown) for maintaining the first, second andthird heating zones in the immediate vicinity of the respective heatersat different temperatures. Heating is achieved using hot water or steam.Thermal oils may also be used. In the vacuum environment of the chamber,heating is achieved by conduction and radiation, and the heaters arevery close to or in contact with the belt.

A lactulose solution is introduced into the apparatus via nozzle 16 atthe end of a fluid line 19 connected to the lactulose solution which islocated externally of the apparatus and connected to fluid input 20.Arrows indicate the direction of flow of solution. The nozzle, belt andheating zones are all located within a vacuum chamber 21 of theapparatus. The nozzle moves in a reciprocating motion at the end of adispenser head 22 mounted on pivot 23 moving back and forth across thebelt as the belt moves forwards, depositing an even layer of solutionover virtually the whole of the width of the belt. Outlines 22 a and 22b show the extent of travel of the dispenser head 22 in operation.

Referring in more detail to FIG. 1, lactulose solution is extruded fromexit point 17 of the nozzle 16 and upon entry into the vacuum chamber,under conditions of elevated temperature and reduced pressure, expandsinto foam 18. The exit point 17 has a diameter of about 5 mm and at atemperature of about 120° C. and a pressure of 50 mbar or less a foam isproduced which typically has a height of around 40-70 mm.

The belt 11 moves slowly in the direction shown by arrow A and the beltspeed is such that when the nozzle has completed its return trip fromone side of the belt to the other and back the belt has advanced by anamount equal to the width of foam produced by the extruded solution. Asa result a foam carpet is laid down on the belt and the extrusion anddrying is continuous. The foam dries as it is moved by the belt throughthe various heating zones under reduced pressure. The first zone is atabout 120° C. and the last at about 40° C., with intermediate zones atintermediate temperatures.

Dried foam at about 40° C. then falls off or is cut off the end of thebelt and falls into a collecting bin 23. The dried foam is optionallysubjected to milling or grinding or other breaking to obtain a lactulosepowder.

The apparatus also has inspection covers 24 and inspection ports 25along its side and is supported by legs 26. Fluid feed apparatus 27comprises a container 28 for holding the solution and motor plus gearbox29 for pumping the solution along fluid line 19.

EXAMPLE 1

A lactulose-containing solution was prepared having 80 percent by weightsolids of which about 70 percent was lactulose. This solution wasintroduced into the vacuum chamber of the apparatus as described abovewith reference to the drawings through a nozzle of 5 mm diameter andinto a heating zone at a temperature of about 120° C. The pressure inthe vacuum chamber was maintained at about 30 mbar. The three heatingzones in the apparatus were maintained at about 120° C., about 80° C.and about 40° C., with a belt speed such that the foam remained withineach area for about 10 minutes.

The lactulose solution introduced into the chamber expanded into a foamof about 50 mm height having a yellowy-white colour and a glisteningappearance. On exiting from the third heating zone, at about 40° C., thefoam had dried to a moisture content of about 4 percent and was brokenup into a free-flowing powder. This powder was suitable for directpackaging into plastic bags or other containers and was found uponsimple mixing with water readily to be reconstituted into alactulose-containing solution.

EXAMPLE 2

The method of Example 1 was repeated with variations in the solidscontent of the lactulose solution, the temperatures in the individualheating zones, the pressure within the vacuum chamber and the belt speed(i.e. the total residence time in all heating zones) and with thefeeding time and temperatures recorded.

The specific conditions and results obtained are shown in the followingtables, and the examples were carried out using apparatus having fourindividual heating zones.

TABLE 1 Test No. 1 2 3 4 Solids content 84 84 84 84 of lactulosesolution, % Temperatures in 120/100/ 80/120/ 80/100/ 80/100/ zones 1-4,° C. 80/40 80/40 80/40 80/40 Vacuum abs, 25 35 35 10 mbar Residencetime, 42 42 42 18 min Feed 36 35 35 37 temperature, ° C. Feeding time, 66 6 6 min Dried Product 0.6255 0.5978 0.6622 0.6744 Quantity, Kg Output,Kg/m²/h 3.91 3.74 4.14 4.22 Colour white white white white Residual 3.01.9 4.4 4.2 moisture, %

TABLE 2 Test No. 5 6 7 8 Solids content 84 84 84 84 of lactulosesolution, % Temperatures in 120/100/ 120/100/ 120/100/ 140/120/ zones1-4, ° C. 80/22 80/22 80/23 100/40 Vacuum abs, 10 10 10 10 mbarResidence time, 18 18 18 19 min Feed 37 38 38 38 temperature, ° C.Feeding time, 6 6 3 6 min Dried Product 0.6669 0.6733 0.3793 0.6784Quantity, Kg Output, Kg/m²/h 4.17 4.21 4.74 4.24 Colour white whitewhite white Residual 4.4 5.0 5.5 3.5 moisture, %

The invention thus provides a method for drying a lactulose solutioninto a powdered form, without the need for swelling or gelling agents orseed crystals, and also provides a powdered form of lactulose that isreadily reconstituted with water to reform a lactulose solution.

1. A method of drying a lactulose solution, comprising introducing the solution into a vacuum chamber at elevated temperature and at reduced pressure so that the solution forms a foam; drying the foam under reduced pressure; and optionally, subjecting the dried foam to a process selected from the group consisting of milling, grinding, breaking and combinations thereof to form a powder.
 2. A method according to claim 1 comprising extruding the solution through a nozzle so that the solution foams as it exits the nozzle.
 3. A method according to claim 1, wherein the foam is dried at a temperature which is reduced over time.
 4. A method according to claim 3 comprising passing the foam through a plurality of drying zones, each zone being at a different temperature, the temperature of the zones reducing from one zone to the next.
 5. A method according to claim 4 comprising passing the foam through a first zone at a temperature of at least 100° C. and passing the foam through a final zone at a temperature of 50° C. or less.
 6. A method according to claim 1 wherein the foam is dried at a temperature which increases and then decreases.
 7. A method according to claim 1 comprising passing the foam through a first zone at a temperature of about 110-130° C. for a period of about 8-15 minutes, passing the foam through a second zone at a temperature of about 70-90° C. for a period of about 8-15 minutes and passing the foam through a third zone at a temperature of about 20-40° C. for about 8-15 minutes.
 8. A method according to claim 1, wherein the pressure in the vacuum chamber is maintained below 50 mbar.
 9. A method according to claim 1, wherein the drying is carried out in a belt dryer within the vacuum chamber and the method comprises evenly distributing the solution over the belt of the dryer.
 10. A method of drying a lactulose solution comprising subjecting the solution to conditions of raised temperature and reduced pressure so that the solution expands into a foam, and drying the foam.
 11. A method according to claim 10 wherein the foam is obtained at a temperature of at least 100° C. and a pressure no greater than 50 mbar. 